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Wednesday 17 Nov 2010A variant of the gene AKT1 influences differential sensitivity to the psychomimetic effects of cannabis in unaffected siblings of patients diagnosed as having psychotic disorders, according to a new study led by researchers in the Netherlands.

Although differences in sensitivity have long been noted, their underlying molecular basis is not understood. AKT1 has been previously associated with schizophrenia. The authors of the current report, published online November 1 in Archives of General Psychiatry, suggest that the AKT1 variant may influence dopaminergic signaling, acting downstream from the dopamine D2 receptor.

The study identified patients in the Netherlands and Belgium diagnosed as having nonaffective psychotic disorder and recruited their unaffected siblings. Study participants were 801 patients, 740 unaffected siblings, and 419 unrelated control individuals for whom the Family Interview for Genetic Studies identified no first-degree relatives with psychotic disorders.

In addition to parents, siblings may have similar experiences in early life, and siblings of patients diagnosed as having psychotic disorders have higher genetic risk for psychosis than the control population.

Investigating the effects of cannabis on positive schizotypy in unaffected siblings (and controls) — as measured by the Structured Interview for Schizotypy-Revised (SIS-R) — is "a powerful and valid approach to examine which genes confer psychosis risk following cannabis use," according to investigators.

These experiences cluster into positive schizotypy items, including magical ideation, illusions, and suspiciousness, and negative schizotypy items, such as social isolation, introversion, restricted affect, and poverty of speech, said Dr. van Winkel.

"Our study used positive schizotypy as the outcome in the unaffected siblings of patients since it was already known that cannabis use is strongly associated with positive schizotypy."

Cannabis use was measured through urinalysis results, with detection up to 1 month or more, and by the Composite International Diagnostic Interview (CIDI) in individuals whose heaviest use preceded their psychosis.

"The CIDI is a structured interview that asks participants to indicate which drugs they have used more than 5 times during their life, approximately how many times they used these drugs, how long their period of most intensive use was, and also what the frequency of use was in this period," Dr. van Winkel explained.

Genes of interest were selected by a literature review and included those associated with schizophrenia, important in dopaminergic neurotransmission, related to cannabinoid signaling, and several implicated in environmental interactions. Initial analyses investigated 42 genes with 152 single-nucleotide polymorphisms (SNPs).

The first analyses looked for relationships between the selected SNPs and cannabis use in the at-risk population (unaffected siblings). Recent use of cannabis was associated with positive schizotypy (P < .0001); but none of the SNPs associated with positive schizotypy were associated with recent cannabis use (P not < .05).

However, 16 SNPs in 12 genes showed significant interactions with recent cannabis use (P < .05), and 3 of these SNPs — 2 in AKT1 and 1 in LRRTM1 — showed particularly strong interactions (P = .0003). When followed up in the 801 patients, only the AKT1 SNP rs2494732 had a "robust and consistent association with CIDI lifetime use, restricted to use preceding onset of psychosis." The relative risk for daily cannabis use for patients with the C/C genotype was 1.90 times that of patients with the T/T genotype.

Comparing patients with unaffected siblings and patients with controls regarding these 3 SNPs, only rs2494732 displayed at least a trend for genetic interaction with cannabis use (interaction P = .040 for case-sibling; interaction P = .057 for case-control).

In unaffected siblings — especially those with the C/C genotype who use cannabis — a high schizotypy score indicates a higher degree of subclinical psychotic experiences. These experiences may include feeling suspicious in some situations, hearing voices occasionally, or believing that songs on the radio refer to themselves.

"These participants are without doubt at a higher than average risk to develop a psychotic disorder, but the chance that they will not develop a psychotic disorder is still much higher," said Dr. van Winkel.

The study authors acknowledge that the significance of their finding "is unclear and requires further replication," noting that the complexity of schizophrenia may require a variety of approaches, such as genome-wide association studies, imaging genetics, epigenetics, animal studies, and gene-environment interactions [like the present analysis] to achieve greater understanding.

"This is a very impressive article," John McGrath, MBBS, MD, PhD, of the Queensland Brain Institute, University of Queensland, Brisbane, and the Queensland Centre for Mental Health Research, Wacol, Australia, told Medscape Medical News. "The AKT1 findings are very thought provoking and now need to be pursued in basic neuroscience platforms and clinical settings."

"It should be noted that SNPs in COMT [gene encoding a major enzyme in dopamine catabolism] were not implicated in this study," added Dr. McGrath. "This is an important finding...[and] it weakens the case that COMT variation mediates cannabis use vs risk of psychosis and suggests that hypotheses related to cannabis use and dopamine metabolism may need to be revised."

The analyses by Dr. van Winkel and GROUP investigators were supported by unrestricted grants from Jansen-Cilag, Eli Lilly and Company, AstraZeneca, and Lundbeck. Dr. McGrath has disclosed no relevant financial relationships.